Peripheral neuropathy is a manifestation of disorders that inflict damage to the peripheral nervous system (PNS), a network of ganglia and neurons that transmit signals between the central nervous system (CNS), i.e. brain and spinal cord, and every other part of the body. Neurons of the PNS rely on Schwann cells for, e.g. myelination, accelerated nerve conduction, nerve development and regeneration, trophic support, production of nerve extracellular matrix, and modulation of neuromuscular synaptic activity. These Schwann cells provide electric insulation by wrapping a protein and lipid-rich myelin sheath around axons of motor and sensory neurons. Given myelin's critical role, it is not surprising that demyelination of peripheral axons is a hallmark of acute and chronic peripheral neuropathies such as Guillain-Barré syndrome (GBS), chronic demyelinating polyneuropathy (CIDP) and multifocal motor neuropathy (MMN) as well as other peripheral nerve pathologies induced by toxins, drugs or systemic diseases, e.g. diabetes.
Peripheral neuropathies can distort signal transmission, causing symptoms that vary with the origin of the neuropathy and type or number of nerves affected. For example, symptoms may depend on whether the disorder affects sensory nerve fibers, which transmit sensory information from the affected area to the CNS, or motor nerve fibers, which transmit impulses and coordinate motor activity from the CNS to a muscle, or both. Peripheral neuropathies can be classified as mononeuropathies, involving damage to one nerve, or polyneuropathies, involving damage of multiple nerves; acute, where symptoms appear suddenly, progress rapidly, and resolve slowly, or chronic, where symptoms begin subtly, and progress slowly. Over 100 different types of peripheral neuropathy have been identified to date. Clinical diagnoses of peripheral neuropathy can be made based on the clinical history of the subject, a physical examination, the use of electromyography (EMG) and nerve conduction studies (NCS), autonomic testing, and nerve biopsies, etc.
Current treatments for peripheral neuropathies are directed at the underlying condition, where possible, and often used in conjunction with symptomatic treatments, such as anti-inflammatory agents, pain management, mechanical aids, and/or surgical intervention, etc. The body also possesses its own regenerative capacity in response to injury or damage of the PNS. After injury to the PNS, Wallerian degeneration of distal nerve stumps occur, followed by Schwann cell degradation of myelin, phagocytosis of extracellular myelin, and recruitment of macrophages for further myelin clearance. Schwann cells can further adapt to pathological situations by its ability to dedifferentiate, proliferate, promote axonal regeneration and redifferentiate, and produce myelin. See Bhatheja et al. (2006) Int. J. Biochem. Cell Biol. 38(12):1995-9. In the course of repair, Schwann cells stimulate, guide axonal regeneration, and target reinnervation, forming a regeneration tube of the axon, known as Bunger's band, by proliferating rapidly and providing the axon with a path to grow along. See Burstyn-Cohen et al. (1998) J. Neurosci 18(21): 8875-8885. While functional nerve regeneration in the PNS can generally be observed (in contrast to CNS which lacks a regenerative mechanism for myelin clearance and axon regeneration), it is often limited or chronically impaired. Novel repair promoting approaches for the PNS are therefore needed.
Recent studies on the CNS have yielded evidence of IgM's direct effect on oligodendrocytes, the myelinating glial cells of the central nervous system. For instance, targeting of oligodendrocyte-reactive IgMκ antibodies to oligodendrocytes was found to promote CNS remyelination (Asakura et al., 1998). Other studies showed that treatment of a non-immune, toxin-induced model of demyelinating disease with pooled human IgM molecules results in a significantly enhanced oligodendrocyte differentiation in the CNS (Bieber et al., 2000; Bieber et al., 2002; Warrington et al., 2007). The discovery of Fc receptors for IgM on oligodendrocytes, their precursor cells, and myelin in the CNS, offers further clues of a possible ligand-receptor interaction (Nakahara et al., 2003).
Knowledge gained from these oligodendrocyte—IgM studies, though meaningful for CNS repair, fails to harness the regenerative capacity of the PNS (which contains no oligodendrocytes). In more relevant studies, administration of human IVIG was found to reduce disease duration in an EAN (autoimmune neuritis) rat model, simulating the PNS-specific, demyelinating Guillain-Barré syndrome (GBS) (Lin et al., 2007). The effects were postulated as being attributable to IVIG's immunomodulatory role and possible anti-inflammatory and secondary bystander axonal loss reduction capability. In a separate study of the humoral immune system, B-cell knockout RID mice exhibited significant delay in macrophage influx, myelin clearance, and axon regeneration after PNS injury. Rapid myelin debris clearance was restored through passive transfer of antibodies from naïve WT mice or anti-PNS myelin antibody, thereby confirming the role of endogenous antibodies in promoting macrophage entrance and phagocytic activity (Vargas et al., 2010). Clinical trials with administration of intravenous immunoglobulins (IVIG) have shown positive effects for GBS, chronic demyelinating polyneuropathy (CIDP) and multifocal motor neuropathy (MMN), with the assumption that treatment in each of these autoimmune or immune-mediated neuropathies was accomplished through IVIG's immunomodulatory role.
The effect of polyclonal IgG on Schwann cells, if any, was heretofore unknown. A question, therefore, remained as to how the regenerative function of Schwann cells could be harnessed for therapeutic purposes in demyelinating, peripheral neuropathies. The present discovery of exogenous polyclonal IgG's ability to induce Schwann cell maturation, differentiation, and myelin production, is an important clarification of mechanism that provides novel approaches to the treatment of all demyelinating peripheral neuropathies.